Method of heightening optical purity of 1-benzyl-3-aminopyrrolidine and salt for used therein

ABSTRACT

The present invention provides a method to improve the optical purity of 1-benzyl-3-aminopyrrolidine having a low optical purity using an inexpensive agent via a simple procedure. The present invention provides a method for improving the optical purity of 1-benzyl-3-aminopyrrolidine including the steps of converting 1-benzyl-3-aminopyrrolidine into an equimolar salt with an optically inactive acid, and recovering the salt as crystals. The present invention also provides a salt of 1-benzyl-3-aminopyrrolidine that is used in the method.

TECHNICAL FIELD

[0001] The present invention relates to a method for improving theoptical purity of 1-benzyl-3-aminopyrrolidine, which is useful as asynthetic intermediate in fine chemicals such as medicines andagricultural chemicals. The present invention also relates to a new saltof 1-benzyl-3-aminopyrrolidine, which is used in the method to improvethe optical purity.

BACKGROUND ART

[0002] The following methods used to improve the optical purity of1-benzyl-3-aminopyrrolidine are well known. For example, racemic1-benzyl-3-aminopyrrolidine is optically resolved with an opticallyactive carboxylic acid derivative (Japanese Unexamined PatentApplication Publication No. 02-218664); an optically active amino acidderivative or an optically active tartaric acid derivative is used as anoptical resolution agent (Japanese Unexamined Patent ApplicationPublication Nos. 09-124595 and 09-176115); and an optically activecamphorsulfonic acid is used as the optical resolution agent (JapaneseUnexamined Patent Application Publication No. 09-216866). However, noneof the above optical resolution agents are readily available and areinexpensive. Therefore, these methods are unsatisfactory for industrialproduction.

[0003] In terms of an alternative method, an optically active materialis converted to a pyrrolidine derivative in order to produce opticallyactive 1-benzyl-3-aminopyrrolidine. However, this compound is oftenracemized during the derivation process; therefore, it is difficult toproduce high-optical-purity 1-benzyl-3-aminopyrrolidine (for example,Japanese Unexamined Patent Application Publication No. 2000-53642, PCTJapanese Translation Patent Publication No. 07-506110, etc.).Consequently, there is a demand for the development of a method toimprove the optical purity of 1-benzyl-3-aminopyrrolidine produced bythese methods.

[0004] In addition to the salt of 1-benzyl-3-aminopyrrolidine with anoptically active acid described above, racemic1-benzyl-3-aminopyrrolidine monohydrochloride (Tetrahedron Letters 42(2001) 5,645), optically active 1-benzyl-3-aminopyrrolidinedihydrochloride (Japanese Unexamined Patent Application Publication No.02-218664), and racemic 1-benzyl-3-aminopyrrolidine monofumarate aredisclosed. However, no method has been reported to improve the opticalpurity of 1-benzyl-3-aminopyrrolidine by forming the salts thereof.

[0005] As described above, a method to improve the optical purity of1-benzyl-3-aminopyrrolidine having a low optical purity using aninexpensive agent via a simple procedure is unknown.

SUMMARY OF THE INVENTION

[0006] In view of the above problems, it is an object of the presentinvention to provide a method to improve the optical purity of1-benzyl-3-aminopyrrolidine having a low optical purity using aninexpensive agent via a simple procedure.

[0007] As a result of intensive study to solve the above problems, thepresent inventors have found that high-optical-purity1-benzyl-3-aminopyrrolidine can be inexpensively and simply produced byconverting 1-benzyl-3-aminopyrrolidine into an equimolar salt with anoptically inactive acid and recovering the salt as crystals, and havesuccessively achieved the present invention.

[0008] The present invention relates to a method to improve the opticalpurity of 1-benzyl-3-aminopyrrolidine. The method includes the steps ofconverting 1-benzyl-3-aminopyrrolidine into an equimolar salt with anoptically inactive acid, and then recovering the salt as crystals.

[0009] The present invention also relates to a salt of1-benzyl-3-aminopyrrolidine represented by general formula (1):

[0010] (wherein HX represents hydrobromic acid, methanesulfonic acid, oracetic acid).

DISCLOSURE OF INVENTION

[0011] The present invention will now be described in detail.

[0012] According to the method used to improve the optical purity of1-benzyl-3-aminopyrrolidine in the present invention,1-benzyl-3-aminopyrrolidine, in particular, its optically activesubstance, is converted into an equimolar salt with an opticallyinactive acid, and the salt is then recovered as crystals.

[0013] Low-optical-purity 1-benzyl-3-aminopyrrolidine used in thepresent invention can be prepared as follows. For example, as isdisclosed in Japanese Unexamined Patent Application Publication No.2000-53642, a 1,2,4-trisubstituted butane derivative is converted into apyrrolidine derivative in the presence of a primary amine, followed byreaction of the pyrrolidine derivative under pressure in the presence ofanother amine. As is disclosed in PCT Japanese Translation PatentPublication No. 07-506110, amino group-protected L-aspartic acid isreduced, and then the product is allowed to react with, for example, athionyl halide. Furthermore, the product is allowed to react with anamine to produce a pyrrolidine derivative, and then the pyrrolidinederivative is deprotected.

[0014] Examples of the optically inactive acid used in the presentinvention include a mineral acid such as hydrochloric acid, hydrobromicacid, phosphoric acid, and sulfuric acid; an organic sulfonic acid suchas methanesulfonic acid; and a carboxylic acid such as acetic acid.These acids may be used alone or in combination. A monovalent acid suchas hydrochloric acid, hydrobromic acid, methanesulfonic acid, and aceticacid is preferably used, because these acids readily form an equimolarsalt with 1-benzyl-3-aminopyrrolidine. In terms of the properties of thecrystals, such as low hygroscopicity and good filterability, hydrobromicacid and methanesulfonic acid are more preferably used.

[0015] The content of the optically inactive acid is not limited, aslong as the optically inactive acid can form an equimolar salt with1-benzyl-3-aminopyrrolidine, and the salt can then be recovered ascrystals. In order to significantly improve the optical purity withoutforming a salt of 1-benzyl-3-aminopyrrolidine with the opticallyinactive acid in a ratio of 1:2 by mole, the content of the opticallyinactive acid is preferably 0.1 molar equivalents to 1 molar equivalent,and more preferably, 0.5 molar equivalents to 0.9 molar equivalents of1-benzyl-3-aminopyrrolidine. The content of the optically inactive acidmay be 1 molar equivalent or less of one optical isomer having a highercontent of 1-benzyl-3-aminopyrrolidine, thereby maximizing theimprovement of the optical purity.

[0016] The procedure to improve the optical purity of the presentinvention is preferably carried out in a solvent. Examples of thesolvent used in the present invention include alcohols such as isopropylalcohol, ethanol, and methanol; polyhydric alcohols such as ethyleneglycol and propylene glycol; esters such as ethyl acetate and methylacetate; hydrocarbons such as toluene and hexane; ethers such as diethylether, tetrahydrofuran, and methyl-tert-butylether; polyethers such asglymes; halogenated hydrocarbons such as methylene chloride; amides suchas dimethylformamide; sulfoxides such as dimethylsulfoxide; and water.Preferably, esters such as ethyl acetate; hydrocarbons such as tolueneand hexane; alcohols such as isopropyl alcohol and ethanol; and waterare used. These solvents may be used alone or in combination.

[0017] The kind, content, and mixing ratio of the solvents may beselected in view of the solubility of the desired salt.

[0018] The methods used to crystallize the equimolar salt of1-benzyl-3-aminopyrrolidine and the optically inactive acid are asfollows:

[0019] (1) An aqueous solution of an optically inactive acid is mixedwith 1-benzyl-3-aminopyrrolidine, and the mixture is then concentratedto remove water, thus crystallizing the salt. A solvent that can form anazeotropic mixture with water (for example, ethyl acetate and toluene)may be used. In this case, water may be removed by azeotropy.

[0020] (2) An optically inactive acid is mixed with1-benzyl-3-aminopyrrolidine in a solvent to crystallize the salt.

[0021] (3) An optically inactive acid is mixed with1-benzyl-3-aminopyrrolidine in a solvent, alternatively, a salt of1-benzyl-3-aminopyrrolidine with an optically inactive acid is dissolvedin a solvent; and then the resultant mixture is cooled to crystallizethe salt.

[0022] (4) An optically inactive acid is mixed with1-benzyl-3-aminopyrrolidine in a solvent; alternatively, a salt of1-benzyl-3-aminopyrrolidine with an optically inactive acid is dissolvedin a solvent. A poor solvent is then added to the resultant mixture tocrystallize the salt. Alternatively, the solvent in the resultantmixture is replaced with a poor solvent to crystallize the salt.

[0023] A suitable method may be selected in view of the combinations ofthe kinds of salt and the solvent. For example, when using an acid suchas hydrochloric acid or hydrobromic acid, both of which are readily usedas an aqueous solution, method (1) is preferably selected. When using anacid such as methanesulfonic acid or acetic acid, both of which aregenerally and readily used in anhydrous form, method (2) is preferablyselected. Furthermore, salt slurry produced by method (1) or (2) may beredissolved by method (3), and then the mixture is cooled to crystallizethe salt. Thus, methods (1), (2), (3) and (4) may be satisfactorilyperformed in combination to crystallize the salt.

[0024] Examples of the solvents used in methods (2), (3), and (4)include the same solvents described above.

[0025] Examples of the poor solvent used in method (4), include tolueneand hexane.

[0026] The salt of 1-benzyl-3-aminopyrrolidine with an opticallyinactive acid used in method (3) or (4) may be prepared by the methoddescribed in the present invention (i.e., method (1), method (2), method(3) wherein an optically inactive acid is mixed with1-benzyl-3-aminopyrrolidine in a solvent, or method (4) wherein anoptically inactive acid is mixed with 1-benzyl-3-aminopyrrolidine in asolvent). The salt of 1-benzyl-3-aminopyrrolidine with an opticallyinactive acid prepared by the above method may be used again in method(3) or (4). Alternatively, the salt of 1-benzyl-3-aminopyrrolidine withan optically inactive acid used in method (3) or (4) may be preparedduring a process to synthesize 1-benzyl-3-aminopyrrolidine in thepresence of an optically inactive acid. The salt of1-benzyl-3-aminopyrrolidine with an optically inactive acid prepared bythe above process may be used in method (3) or (4).

[0027] When a salt of 1-benzyl-3-aminopyrrolidine with an opticallyinactive acid is dissolved in a solvent, for example, the mixture may beheated. Although the temperature of the mixture during dissolution isnot limited, the dissolution may be appropriately performed at atemperature that allows 1-benzyl-3-aminopyrrolidine and the opticallyinactive acid to be dissolved in the solvent or the mixed solvent, orhigher.

[0028] The temperature of the solution during the crystallization inmethods (1) to (4) may be suitably determined in view of the kinds ofsalt and solvent, and is not limited. The crystallization may bepreferably performed at a temperature lower than the temperature thatallows 1-benzyl-3-aminopyrrolidine and the optically inactive acid to bedissolved in the solvent or the mixed solvent. The temperature of thesolution during the crystallization may be appropriately determined inview of the desired amount of precipitation.

[0029] The crystals of the equimolar salt of 1-benzyl-3-aminopyrrolidineand the optically inactive acid precipitated by the crystallizationmethod described above can be separated by, for example, filtration torecover the crystals.

[0030] Since the equimolar salt of 1-benzyl-3-aminopyrrolidine and theoptically inactive acid crystallized by the method has not only a highoptical purity but also a high chemical purity, the salt can be useddirectly as a material for fine chemicals such as medicines andagricultural chemicals. Furthermore, the salt may be treated with a basesuch as an alkali metal hydroxide to isolate1-benzyl-3-aminopyrrolidine. The product may then be, for example,extracted, concentrated, and distilled to produce oily1-benzyl-3-aminopyrrolidine having a high optical purity.

[0031] Among the equimolar salts of 1-benzyl-3-aminopyrrolidine and theoptically inactive acids, a salt with hydrobromic acid, methanesulfonicacid, or acetic acid, in particular, its optically active substance is anew compound in which the present inventors found its utility in themethod to improve the optical purity of 1-benzyl-3-aminopyrrolidine, thesalt being represented by general formula (1):

[0032] (wherein HX represents hydrobromic acid, methanesulfonic acid, oracetic acid).

BEST MODE FOR CARRYING OUT THE INVENTION

[0033] The present invention will now be described in detail withreference to the following examples, which do not serve to limit thescope of the present invention.

[0034] The optical purity in the following Examples was determined bythe following method. A solution (0.2 mL) of 0.4% GITC (GITC:2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl thiocyanate) in acetonitrilewas added to a solution (0.1 mL) of 0.18% 1-benzyl-3-aminopyrrolidine inacetonitrile. (When the optical purity of a salt of1-benzyl-3-aminopyrrolidine with an optically inactive acid wasdetermined, oily 1-benzyl-3-aminopyrrolidine prepared by the followingprocedure was used for the analysis. The salt of1-benzyl-3-aminopyrrolidine with an optically inactive acid wasdissolved in water, and sodium hydroxide was then added to alkalify thesolution. The solution was extracted with toluene and then concentratedto recover oily 1-benzyl-3-aminopyrrolidine.) The solution containing amixture of GITC and 1-benzyl-3-aminopyrrolidine was allowed to react for10 minutes at room temperature, and a solution (0.1 mL) of 0.2%ethanolamine in acetonitrile was then added to the solution and allowedto stand for 3 minutes. Subsequently, the solution was diluted with0.05% aqueous phosphoric acid solution (1.0 mL) to prepare a samplesolution. The sample solution (5 μL) was injected into a highperformance liquid chromatograph (HPLC). The optical purity wasdetermined by the ratio of peak areas measured by liquid chromatography.The column used for the analysis was a CAPCELL PAK C18 SG120 (SISEIDO),4.6 mm in diameter by 250 mm in length. The mobile phase was a mixture(62:38 by volume) of an aqueous solution with a pH of 4 (the aqueoussolution was prepared by adding a 5% aqueous acetic acid solution to a0.03% aqueous ammonia solution) and methanol. The flow rate was 1.0mL/min., the temperature of the column was 30° C., and the detectionwavelength was 254 nm in the ultraviolet region. The detection time ofthe GITC derivative of (R)-1-benzyl-3-aminopyrrolidine was 25.5 minutes,and the detection time of the GITC derivative of(S)-1-benzyl-3-aminopyrrolidine was 28.5 minutes.

EXAMPLE 1

[0035] 1-Benzyl-3-aminopyrrolidine (1.50 g) having a chemical purity of89.9 weight percent and an optical purity of 88.8% e.e. ((R)enantiomeric excess) was dissolved in ethyl acetate (10 g). Concentratedhydrochloric acid (0.75 g, i.e., an amount of 1.0 molar equivalent ofthe (R)-1-benzyl-3-aminopyrrolidine) was added to the mixture. Thesolution was concentrated under reduced pressure to remove water. Ethylacetate (20 mL) was added to the concentrated mixture, and the mixturewas further concentrated. Ethyl acetate (20 mL) was added to theresultant mixture, and the mixture was left for crystallization. Thecrystals were filtrated and then dried to recover1-benzyl-3-aminopyrrolidine monohydrochloride (1.48 g). The opticalpurity was increased to 93.6% e.e. ((R) enantiomeric excess).

EXAMPLE 2

[0036] As in Example 1, 1-benzyl-3-aminopyrrolidine monohydrobromide(1.68 g) was produced but 48% hydrobromic acid (1.21 g, i.e., an amountof 1.0 molar equivalent of the (R)-1-benzyl-3-aminopyrrolidine) was usedinstead of concentrated hydrochloric acid. The optical purity wasincreased to 96.0% e.e. ((R) enantiomeric excess).

[0037] 1-Benzyl-3-aminopyrrolidine monohydrobromide

[0038] Melting point: 103° C. to 107° C.

[0039] IR (KBr) cm⁻¹: 2,149, 1,613, 1,526, 1,467, 1,408, and 1,379

EXAMPLE 3

[0040] 1-Benzyl-3-aminopyrrolidine (1.51 g) having a chemical purity of89.9 weight percent and an optical purity of 88.8% e.e. ((R)enantiomeric excess) was dissolved in ethyl acetate (10 g). Acetic acid(0.41 g, i.e., an amount of 0.94 molar equivalents of the(R)-1-benzyl-3-aminopyrrolidine) was added to the mixture. Hexane (30mL) was added to the solution and the mixture was left forcrystallization. The crystals were filtrated and then dried to recover1-benzyl-3-aminopyrrolidine monoacetate (1.48 g). The optical purity wasincreased to 93.4% e.e. ((R) enantiomeric excess).

[0041] 1-Benzyl-3-aminopyrrolidine monoacetate

[0042] Melting point: 90° C. to 95° C.

[0043] IR (KBr) cm⁻¹: 2,224, 1,647, 1,541, 1,474, 1,352, and 1,154

EXAMPLE 4

[0044] 1-Benzyl-3-aminopyrrolidine (1.42 g) having a chemical purity of89.9 weight percent and an optical purity of 88.8% e.e. ((R)enantiomeric excess) was dissolved in ethyl acetate (5 g). A solutionprepared by dissolving methanesulfonic acid (0.49 g, i.e., an amount of0.75 molar equivalents of the (R)-1-benzyl-3-aminopyrrolidine) in ethylacetate (5 g) was added to the mixture. As soon as the solution wasadded, the crystals precipitated. The crystals were filtrated and thendried to recover 1-benzyl-3-aminopyrrolidine monomethanesulfonate (1.40g). The optical purity was increased to 95.4% e.e. ((R) enantiomericexcess).

[0045] 1-Benzyl-3-aminopyrrolidine monomethanesulfonate

[0046] Melting point: 97° C. to 102° C.

[0047] IR (KBr) cm⁻¹: 2,149, 1,615, 1,549, 1,453, 1,240, and 1,148

EXAMPLE 5

[0048] 1-Benzyl-3-aminopyrrolidine (3.38 g) having a chemical purity of100 weight percent and an optical purity of 90.5% e.e. ((R) enantiomericexcess) was dissolved in isopropyl alcohol (15 g). A 48% solution ofhydrobromic acid (3.05 g, i.e., an amount of 0.99 molar equivalents ofthe (R)-1-benzyl-3-aminopyrrolidine) was added to the solution. Themixture was concentrated by about 5 g under reduced pressure to removewater. The concentrated mixture was stirred at room temperature to allowcrystallization. The crystals were filtrated and then dried to recover1-benzyl-3-aminopyrrolidine monohydrobromide (0.95 g). The opticalpurity was increased to 99.6% e.e. ((R) enantiomeric excess).

EXAMPLE 6

[0049] 1-Benzyl-3-aminopyrrolidine (10.17 g) having a chemical purity of90.3 weight percent and an optical purity of 89.8% e.e. ((R)enantiomeric excess) was dissolved in ethanol (30 g). A 48% ofhydrobromic acid (7.84 g, i.e., an amount of 0.94 molar percent solutionequivalents of the (R)-1-benzyl-3-aminopyrrolidine) was added to thesolution. The mixture was concentrated under reduced pressure to removewater. Ethyl acetate (59 g) was then added to the mixture to allowcrystallization. The resultant slurry was heated to about 70° C. inorder to dissolve the crystals entirely. The solution was graduallycooled to allow crystallization. The crystals were filtrated and thendried to recover 1-benzyl-3-aminopyrrolidine monohydrobromide (6.15 g).The optical purity was increased to 100% e.e. ((R) enantiomeric excess).

EXAMPLE 7

[0050] 1-Benzyl-3-aminopyrrolidine (10.17 g) having a chemical purity of90.3 weight percent and an optical purity of 89.8% e.e. ((R)enantiomeric excess) was dissolved in ethanol (30 g). Methanesulfonicacid (4.47 g, i.e., an amount of 0.94 molar equivalents of the(R)-1-benzyl-3-aminopyrrolidine) was added to the solution. The ethanolwas removed under reduced pressure. Ethyl acetate (54 g) was then addedto the mixture to allow crystallization. The resultant slurry was heatedto about 79° C. in order to dissolve the crystals entirely. The solutionwas gradually cooled to allow crystallization. The crystals werefiltrated and then dried to recover 1-benzyl-3-aminopyrrolidinemonomethanesulfonate (12.12 g). The optical purity was increased to96.1% e.e. ((R) enantiomeric excess).

[0051] The 1-benzyl-3-aminopyrrolidine monomethanesulfonate (2 g) wasdissolved in water (5 mL). And then 30% sodium hydroxide was added tothe solution to isolate 1-benzyl-3-aminopyrrolidine. The solution wasextracted with toluene (20 mL) and then concentrated. Thus, oily1-benzyl-3-aminopyrrolidine (1.10 g) was recovered.

INDUSTRIAL APPLICABILITY

[0052] According to the present invention, as described above, theoptical purity of 1-benzyl-3-aminopyrrolidine having a low opticalpurity can be improved with an inexpensive agent via a simple procedure.

1. A method for improving the optical purity of1-benzyl-3-aminopyrrolidine, comprising the steps of: converting1-benzyl-3-aminopyrrolidine into an equimolar salt with an opticallyinactive acid; and recovering the salt as crystals.
 2. The methodaccording to claim 1, wherein the 1-benzyl-3-aminopyrrolidine is anoptically active substance.
 3. The method according to claim 2, whereinthe content of the optically inactive acid is 1 molar equivalent or lessof one optical isomer having a higher content of1-benzyl-3-aminopyrrolidine.
 4. The method according to any one ofclaims 1 to 3, wherein the step of recovering comprises: removing waterin a reaction mixture containing an aqueous solution of the opticallyinactive acid to crystallize the salt by concentration of the mixture.5. The method according to any one of claims 1 to 3, wherein the step ofrecovering comprises: mixing 1-benzyl-3-aminopyrrolidine with theoptically inactive acid in a solvent to crystallize the salt.
 6. Themethod according to any one of claims 1 to 3, wherein the step ofrecovering comprises: mixing 1-benzyl-3-aminopyrrolidine with theoptically inactive acid in a solvent, or dissolving a salt of1-benzyl-3-aminopyrrolidine with the optically inactive acid in asolvent; and cooling the mixture to crystallize the salt.
 7. The methodaccording to any one of claims 1 to 3, wherein the step of recoveringcomprises: mixing 1-benzyl-3-aminopyrrolidine with the opticallyinactive acid in a solvent, or dissolving a salt of1-benzyl-3-aminopyrrolidine with the optically inactive acid in asolvent; and adding a poor solvent to the mixture, or replacing thesolvent with a poor solvent to crystallize the salt.
 8. The methodaccording to any one of claims 1 to 7, wherein the optically inactiveacid is at least one acid selected from the group consisting ofhydrochloric acid, hydrobromic acid, methanesulfonic acid, and aceticacid.
 9. The method according to claim 8, wherein the optically inactiveacid is hydrobromic acid or methanesulfonic acid.
 10. A salt of1-benzyl-3-aminopyrrolidine represented by general formula (1):

(wherein HX represents hydrobromic acid, methanesulfonic acid, or aceticacid).
 11. The salt of 1-benzyl-3-aminopyrrolidine according to claim10, wherein the salt is an optically active substance.